Type IIa receptor protein tyrosine phosphatases (RPTPs) are cell surface receptors important for nervous system development, function and repair (1-3). Vertebrate family members (RPTPσ, LAR and RPTPδ) and invertebrate orthologues (e.g. Drosophila DLAR) localise to axonal growth cones, regulating neuronal growth and guidance and participating in excitatory synapse formation and maintenance (1, 4-8). RPTPσ−/− mice exhibit neurological and neuroendocrine defects (9-10) as well as increased nerve regeneration (11-15), while RPTPδ-deficient mice show impaired learning and memory (16); RPTPσ and δ double-mutant mice have a developmental loss of motor neurons leading to paralysis (17).
Type IIa RPTP extracellular regions interact with HSPGs and CSPGs (5, 7, 12, 18). These proteoglycans modulate neuronal growth, guidance and connectivity, typically with CSPGs inhibiting and HSPGs promoting axon extension (19-23). Up-regulation of CSPGs in glial scar tissue after neural injury is an important factor limiting CNS axon sprouting and regeneration (2, 21, 24-25). In adult mouse dorsal root ganglion (DRG) sensory axons, this CSPG inhibitory effect is mediated, at least in part, by RPTPσ (12). In contrast, in developing chick retinal ganglion cell axons, RPTPσ was reported to promote growth in response to basal lamina (26). These observations posed a potential conundrum, namely that of RPTPσ interactions eliciting opposing effects on neuronal outgrowth.